Acute and chronic neurological diseases can be caused by a number of different factors. However, many of these diseases are characterized by cell death in specific regions of the central nervous system.
Neurological diseases are a group of maladies that afflict a significant portion of the human population. The medical and socio-economic impacts of these diseases are significant. Although the etiology of each acute and chronic neurological disease is likely different, one common feature that many share is rapid or progressive irreversible cell death in specific regions of the central nervous system (Standaert, D. G.; Young, A. B. In Goodman & Gilman's The Pharmacological Basis of Therapeutics, Tenth Edition; Hardman, J. G.; Limbird, L. E., Eds.; McGraw-Hill: New York, 2001; Chapter 22, pp 549-568; Mattson, M. P. Nature Rev. Mol. Cell. Biol. 2000, 1, 120-129). Compelling evidence is emerging that neuron cell death occurs in acute neurological diseases, such as stroke and trauma (Raghupathi, R.; Graham, D. I.; McIntosh, T. K. J. Neurotrauma 2000, 17(10), 927-38) and in neurodegenerative diseases, such as Parkinson's disease-PD (Vila, M.; Wu, D. C.; Przedborski, S. Trends in Neuroscience 2001, 24(11), S49-S55), Huntington's disease-HD (McMurry, C. T. Trends in Neuroscience 2001, 24(11), S32-S38), amyotrophic lateral sclerosis—ALS (Beckman, J. S.; Estéves, A. G.; Crow, J. P. Trends in Neuroscience 2001, 24(11), S15-S20), and human immunodeficiency virus associated dementia—HAD (Kaul, M.; Garden, G. W.; Lipton, S. A. Nature 2001, 410, 988-994). Studies have also suggested that cell death occurs in Alzheimer's disease—AD (Eldadah, B. A.; Faden, A. I. J. Neurotrauma 2000, 17(10), 811-829). Albeit, neurons present in AD may be chronically dysfunctional without necessarily undergoing active cell death (Selkoe, D. J. Nature 1999, 399 (Suppl), A23-A30).
Most current approaches to developing treatments for neurological diseases, such as stroke, Parkinson's disease (PD), Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and HIV-associated dementia (HAD) target mechanisms that are hypothesized to be involved in the initiation-phase of the disease. For example, current approaches involve using compounds that attempt to inhibit the initiation of toxicity caused by aggregation of α-synuclein in PD, or aggregation of β-amyloid, tau, and/or ApoE in AD, or aggregation of huntingtin protein in HD, or oxidative stress from reactive oxygen species in ALS, or excessive extracellular excitotoxins, such as glutamate, in stroke or trauma. An alternative approach is to target basic cell death machinery that may be activated as a result of a cellular insult. Current approaches are directed towards a specific death process called apoptosis involving cysteine proteases called caspases. However, a number of recent studies establish that many cell death paradigms, especially those associated with neurodegeneration, involve non-apoptotic/caspase-independent mechanisms.
Therefore, there is a need in the art for compositions and methods to prevent or treat cellular necrosis including cellular necrosis associated with neurodegeneration.